Isolation, Structure Determination, and Synthesis of Neodysiherbaine A, a New Excitatory Amino Acid from a Marine Sponge

Abstract

[structure: see text] A new excitatory amino acid, neodysiherbaine A (2), was isolated as a minor constituent of the aqueous extract from the marine sponge Dysidea herbacea. The structure was deduced by spectroscopic methods and established unambiguously by the total synthesis. The present synthesis, including as a key step cross-coupling of the 6/5-bicyclic core with an amino acid residue, is useful in constructing its structural analogues.

Novel Analogs and Stereoisomers of the Marine Toxin Neodysiherbaine with Specificity for Kainate Receptors

“…KARs agonists are known to be potent convulsants (Ben-Ari and Cossart, 2000), and DH, the first marine toxin isolated from D. herbacea, exhibits the most potent seizurogenic activity of any excitatory amino acid (Sakai et al, 1997). Most of the subsequent analogs of DH elicit varying degrees of convulsant behaviors; MSVIII-19, as an exception, produced subseizure-stereotyped behavior followed by unresponsiveness (Sasaki et al, 1999;Sakai et al, 2001a). 8,9-Epi-neoDH also fails to elicit convulsive behavior even at high doses, probably due to its very low affinity for KARs.…”

“…Uncontrolled chirality in the synthetic pathway for neoDH yielded two analogs of the marine toxin, 4-epi-neoDH and 2,4-epineoDH, in which the L-glutamate backbone in neoDH had altered stereochemistry (Sakai et al, 2001a) (Fig. 1); therefore, they seemed unlikely to bind KARs with significant affinity.…”

“…We previously showed that dysiherbaine (DH), a marine toxin from the sponge Dysidea herbacea, is a high-affinity, subunit-selective KAR agonist and consequently a potent convulsant (Sakai et al, 1997(Sakai et al, , 2001b. DH shares a glutamate congener with other KAR agonists such as kainate and domoate, but it is distinct in that it contains a tetra-substituted hydrofuropyran ring system with two functional groups, at the C8 and C9 positions, that largely control selectivity for AMPA and kainate receptors (Sasaki et al, 1999;Sakai et al, 2001a). Further characterization of a natural analog of DH, neodysiherbaine (neoDH), and a C8/C9 dideoxy synthetic analog of DH, MSVIII-19, revealed that slight structural modifications cause significant changes in the pharmacological activity, including generation of a functional antagonist for GluR5-containing receptors in MSVIII-19 (Sasaki et al, 1999;Sakai et al, 2001a;Sanders et al, 2005).…”

Developmental Biology of Neoplastic Growth

“…The terrestrial excitotoxin acromelic acid, from the Japanese mushroom Clitocybe acromelalga, also falls into this structural class. More recent studies discovered two new natural iGluR ligands, dysiherbaine and neodysiherbaine A (Sakai et al 1997(Sakai et al , 2001a, underscoring the potential utility of screening marine benthic organisms for neuroactive molecules. These molecules are structurally distinct from the kainoids and thus constitute a third family of marine-derived ligands for ionotropic glutamate receptors.…”

1-Deoxynojirimycin Derivatives from the Marine Sponge Lendenfeldia chondrodes

“…In the course of the study we have isolated neodysiherbaine A [16], and several new betaines such as dysibetaine [17], dysibetaine PP, dysibetaine CPa and CPb [18], and demonstrated that this sponge is a rich source of novel amino acid derivatives of some biomedical interests. In this paper, we deal with isolation and structure elucidations of deoxynojirimycin derivatives: 1-deoxynojirimycin-6-phosphate (1) and its N-methyl derivative (2) from this sponge.…”